Despite marked advances in the diagnosis and treatment of breast cancer, patients with basal-like breast cancer (BBC), an aggressive subtype of breast cancer, continue to be confronted with limited treatment options due to current lack of molecular targets in this tumor type. Therefore, the identification of a “druggable” target that is specifically required for basal-like breast tumors is one of the most pressing challenges facing cancer researchers today. The inventors recently identified maternal embryonic leucine zipper kinase (MELK), a novel oncogenic kinase that emerged from an unbiased, in vivo tumorigenesis screen, as a therapeutic target in BBC.
MELK is an atypical member of the AMPK family. While MELK has been implicated in regulating cell cycle progression, cellular proliferation, mitosis, apoptosis, and mRNA splicing (Badouel et al. (2006) Cell Cycle 5:883-889 and Badouel et al. (2010) Exp. Cell Res. 316:2166-2173), the exact function of MELK is unknown. MELK is overexpressed in a number of cancers, including cancers of the colon, breast, ovaries, pancreas, prostate, and brain (Gangulu, R., et al. (2014) Mol. Cancer Ther. 13(6), 1393-1398). In particular, MELK is highly overexpressed selectively in the BBC subtype. Preliminary data shows that overexpression of wild type MELK induces robust oncogenic transformation both in vitro and in vivo with a transforming potency comparable to that of a highly oncogenic mutant allele of PIK3CA. Even more striking is the finding that only human BBC cells, but not luminal breast cancer cells or normal non-cancerous cells, depend on MELK for proliferation. Notably, the kinase activity of MELK is required for its transforming activity as well as for the survival and proliferation of BBC cells. Thus, MELK is potentially a novel oncogenic driver of basal-like breast carcinoma and a promising target for small molecule-based therapeutic intervention.
Because overexpression of MELK has been associated with a number of cancers, there remains a need to develop small molecule-based therapeutic agents that target MELK and that can be used in the treatment of cancers such as BBC that are specifically dependent on MELK. There also remains a need to develop preclinical models for evaluating the efficacy of candidate therapeutic agents against MELK in vivo, and for assessing on-target effects and side-effects of systemic loss of MELK in vivo.